This invention relates to ophthalmic formulations useful in controlling and lowering intraocular pressure (IOP) in the treatment of glaucoma. The formulations of the present invention are characterized as long lasting (sustained release) and are initially and continually comfortable to the eye. Specifically, the invention relates to formulations of the above characteristics which comprise, inter alia, a basic active and a cationic exchange resin (finely divided) dispersed in an aqueous solution or gel of an acidic, mucomimetic polymer. Such resulting aqueous gel or pourable liquid formulations are characterized by controlled cationic-anionic interactions, which appear to be responsible for the resulting comfort and sustained release properties. This invention also relates to methods of treatment which comprise administering the described compositions when indicated for treating ocular hypertension and glaucoma.
The term "basic active" means the active ingredient or ingredients in the disclosed formulations which have the desired effect on intraocular pressure and which bear, or are capable of bearing, a positive charge during formulation of the final product or as formulated in the final product form. Thus, the term basic, or cationic, active is descriptive for purposes of the disclosure and claims.
Such basic actives include all presently known beta blockers which demonstrate the requisite cationic charge and IOP effect. Typically, such beta blockers are represented by the following generic structure, which structure also represents the beta blocker basic actives of the present disclosure: EQU R.sup.1 --O--CH.sub.2 --CH(OH)--CH.sub.2 --NR.sup.2 R.sup.3(I)
wherein:
R.sup.1 is a substituted or unsubstituted cyclic or aliphatic moiety; cyclic moieties include mono- and polycyclic structures which may contain one or more heteroatoms selected from C, N, and O; R.sup.2 and R.sup.3 are independently selected from H and substituted and unsubstituted alkyl. With regard to Structure (I), above, the following references are incorporated herein by reference: Annular Reports in Medicinal Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 26,1570-1576; ibid., 1984, 27, 503-509; ibid., 1983, 26, 7-11; ibid., 1983, 26, 1561-1569; ibid., 1983, 1109-1112; ibid., 1983, 26, 950-957; ibid., 1983, 26, 649-657; and ibid., 1983, 26, 352-357. Representative of such basic actives are: betaxolol, timolol, befunolol, labetalol, propanolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotinolol (S-596), diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol, and the like. PA1 The cationic exchange resin component is dispersed in water. The basic active component is then added with stirring. The polyanionic polymer component is then added. The resulting product has a viscosity ranging from 1000 to 300,000 cps depending on the anionic polymer concentration. The resulting pH is 3.0 to 8.5, which may be adjusted, if necessary, with HCl or NaOH. PA1 The cationic exchange resin component is dispersed in 10 to 50 vol. percent of total water taken in formulation, and then basic active is dispersed and/or dissolved with stirring. The polyanionic polymer, as an aqueous dispersion, is added until the desired pH of the product is obtained. The pH of the product can be adjusted to the desired value by varying basic active/polymer/resin ratio. If desired, final pH of product can be adjusted with addition of either NaOH or HCl. The preferred pH range for ophthalmic formulations is from 3.0 to 8.5. The final product is a dispersion, which may require high energy mixing to break any agglomeration to achieve uniformity. Other formulation ingredients are then added with mixing. The resulting product has a viscosity ranging from 1.0 to 20,000 cps depending on the anionic polymer concentration. PA1 The basic active, the ion exchange resin, and the polyanionic polymer are combined in water and, following mixing, are lyophilized to a powder. Fillers like mannitol and other materials may be added to facilitate the freeze/drying process according to techniques well known to those skilled in the art. The anhydrous salts produced in this manner an then be formulated or reconstituted to aqueous gels and liquids, or can be formulated and shaped as ocular inserts. The lyophilized powder can also be combined with a nonaqueous vehicle to form an ophthalmic ointment. PA1 Such anhydrous salt embodiments of the present invention can also be prepared by extracting the initial aqueous dispersion with an organic solvent such as ethanol, chloroform, benzene, or the like, and evaporating the organic solvent to produce the desired salt complex. The resulting product is substantially equivalent to the above-described lyophilized product.
The definition of basic active also includes the following classes of drugs which are used in treatment of ocular hypertension and glaucoma: pilocarpine; epiniphrine; proepinephrine; norepinephrine; pronorepinephrine; clonidine; and clonidine derivatives, for example, p-aminoclonidine and p-acetoamidoclonidine.
Thus, in summary, the basic active component of the present invention is defined by its intraocular pressure lowering effect or static control thereof, and by its cationic nature in an aqueous medium in the pH range of from 3.0 to 8.5. The following patent publications, which are incorporated herein by reference, further representatively demonstrate the basic actives of the present invention: U.S. Pat. Nos. 4,252,984; 3,309,406; 3,619,370; 3,655,663; 3,657,237; 4,012,444; 3,663,607; 3,836,671; 3,857,952; 3,202,660; and 2,774,789.